Project Summary Undiagnosed Diseases (UD) are constellations of significant signs, symptoms and/or test results that are seen by specialists over time without discovery of their cause(s), and for which diagnostic procedures and tests have been exhausted. The goal of the Undiagnosed Disease Network (UDN) is to diagnose UDs and bring answers that give afflicted individuals hope and ways to improve their health. Our Vanderbilt UDN Clinical Site (VCUD) is an ideal milieu of excellent patient oriented care, and collaborative research. We formed the VCUD by combining unique Vanderbilt resources with UDN resources to diagnose difficult UDs. Vanderbilt resources include: 1) a productive Clinical and Translational Science Award that hosts a large Clinical Research Center (CRC) that has grown, evolved, and developed an outstanding cohort of clinicians and physician scientists, 2) a strong, dedicated group of Pediatricians, Internists, Neurologists and Geneticists, 3) bioinformatics experts, 4) the BioVU DNA databank and experts, 5) structural biology investigators, 6) our EMR and REDCap database, and 7) a strong focus on educating and training the next generation who will help sustain the UDN over the long-term. We have combined our VCUD team (physicians, bioinformatics experts, research scientists, Study Coordinator, NPs, GCs), with UDN resources to diagnose UD patients by the following: A) gathering and analyzing clinical data to form differential diagnoses (clinical hypotheses), B) analyzing next generation sequencing and other test data to form testable gene hypotheses, C) utilizing unique VUMC resources including BioVU, PrediXcan, and Structural Biology to prioritize candidate variants (CV), D) determining the functional effects of non-coding CV, E) testing and merging our clinical and genetic hypotheses to identify concordant disorders and CV that cause the patients' UD, and F) using VCUD Studios to discover new diseases and promote translational research to determine mechanisms and lead to treatments. Using this approach, we have diagnosed 39/50 UDN cases evaluated by our VCUD to date. We hypothesize that we can use VCUD teams to merge patient care with translational research by synergistically combining them with distinct VUMC resources to more efficiently diagnose and treat UD patients. Our VCUD structure will provide the workflow, throughput, and passion needed to test our hypotheses and diagnose and provide treatment recommendations. We will enhance all these activities in the Phase II (UO1) expansion through collaborations with the UDN, the Veteran's Administration, Precision Medicine Projects and health care insurers, to produce an evolving and more sustainable model. Thus, we will accelerate merging patient oriented specialty care with translational research to improve the diagnosis, care, and understanding of patients with UD by our specific aims to: 1) Improve the diagnosis and care of UD patients of all ages, 2) Determine causes of and improve treatment options for UD, and 3) Test the hypothesis that BioVU and Structural Biology can be used as an integrated approach to identify causative variants in UDN patients. !